Clinical aspects of epilepsy-associated - the ...

3rd Congress of the European Academy of Neurology

           Amsterdam, The Netherlands, June 24 – 27, 2017

                              Teaching Course 2

             Autoimmune causes of epilepsy - Level 3

        Clinical aspects of epilepsy-associated
                      antibodies
                               Bastien Joubert
                                   Lyon, France

Email: bastien.joubert@gmail.com

Conflict of interest:
The author has no conflict of interest in relation to this manuscript.

Introduction

Immune-mediated epilepsy encompasses a wide range of diseases,

including acute disseminated encephalomyelitis, Rassmussen encephalitis,

multi-system inflammatory disorders such as sarcoidosis or systemic lupus

erythematosus, paraneoplastic neurological disorders (PNS) and auto-

immune encephalitis (AE). Among those entities, PNS and AE stand out

due to their association with a broad range of specific anti-neuronal

antibodies1,2. Such antibodies enable clinicians to discriminate patients

into groups with distinct clinical presentations and potentially specific

pathophysiological processes1. Therefore, the characterization of the

antigens targeted by those autoantibodies helps to understand the

mechanistic underlying such diseases (Topic 1), and to guide the

management of the patients (Topic 4). Also, as our knowledge about those

rare diseases grows, some clinical features appear to depend on the

antigen targeted by autoantibodies found in the patients and a spectrum

of clinical syndromes defined by specific autoantibodies is beginning to

emerge.

PNS represent a rare complication of cancers and are in most cases

associated with specific autoantibodies grouped under the name of

onconeural antibodies (ONA)3. ONA target intracellular antigens (with the

notable exception of anti-Tr/DNER antibodies) and are each associated

with a more or less wide range of neurological disorders and cancers2.

                                     1

Among PNS, the development of seizures exclusively reflects the

occurrence of paraneoplastic limbic encephalitis (PLE). PLE is caused by

inflammation of the temporo-mesial structures and associates mesial

temporal lobe epilepsy, cognitive impairment and behavioural disorders.

PLE is mostly associated with anti-Hu, anti-CV2, anti-Ma24–7. The

potentially associated, non-limbic symptoms and the overall neurological

prognosis differ according to which antibody is found8. However, to date

no clear-cut difference can be made according to ONA specificity

regarding the clinical expression and outcome of paraneoplastic LE-related

epilepsy.

AE by contrast not always associate with cancers and are characterized by

the presence of autoantibodies nearly all targeting neuronal cell-surface

antigens, mostly proteins involved in synaptic transmission (Topic 1). As

their development seems to involve mechanistic effects exerted by the

autoantibodies on the synaptic proteins they target, they often respond to

immunosuppressive treatment and their prognosis is usually better than

ONA-associated PNS1. The majority of the patients develop acute

encephalitis with limbic symptoms including temporal lobe epilepsy,

although a much wider range of symptoms can be observed1. Brain

magnetic resonance imaging (MRI) may display temporo-mesial T2-

weighted hyperintensities, and cerebrospinal fluid examination may show

pleiocytosis or oligoclonal bands; however, both examinations may be

devoid of abnormalities without challenging the diagnosis. Electro-

encephalographs (EEG) are helpful when demonstrating fronto-temporal

focalisation, but both sensitivity and specificity are low in this context.

Furthermore, some patients may develop a clinical and radiological

syndrome highly suggestive of autoimmune encephalitis with CSF analysis

demonstrating CNS inflammation, but without any detectable anti-

                                    2

neuronal antibodies (Topic 3). Conversely, autoantibodies against neuronal

antigens such as GluR3 (glutamate receptor subunit 3) can be found in

patients with protracted CNS inflammation or refractory, non-autoimmune

epilepsy9. The production of such autoantibodies is probably secondary

to blood-brain barrier disruption and exposure of neuronal antigens to

the immune system and their detection should not lead to the improper

diagnosis of autoimmune encephalitis. Considering those diagnostic

challenges, a set of clinical criteria has been developed recently in order

to improve diagnosis accuracy in patients suspected of limbic ence-

phalitis10. Over the previous decade, an increasing number of anti-

neuronal autoantibodies have been described in patients with auto-

immune encephalitis. Consequently, the accumulating data on patients

with autoimmune encephalitis has brought out specificities of clinical

presentation and outcomes according to the antigen targeted by the

autoantibodies found in the patients CSF or sera. Such specificities include

seizure-related clinical manifestations as well as the responsiveness to

antiepileptic drugs, as it will be developed below.

Antibodies      targeting     the    n-methyl-D-aspartate         (NMDA)-

sensitive glutamatergic receptor

Antibodies against the NMDA receptor (anti-NMDAR antibodies) are

associated with an acute encephalitic syndrome predominantly affecting

young women with a stereotyped course with viral-like prodromal

symptoms, usually followed by psychiatric symptoms and cognitive

disturbances. Only after appear decreased responsiveness, agitation,

catatonia, dysautonomic features and abnormal movements11. Seizures are

usually seen since the early stages, and can be either partial or

generalized. Seizures are sometimes difficult to distinguish from abnormal

                                     3

movements, the distinction between the two sometimes requiring EEG

recording. Status epilepticus is common. In the management of

antiepileptic drugs, and particularly in the context of intensive care, drug

escalation must be cautious, as, 1) seizures can be difficult to distinguish

from abnormal movements, and 2) epilepsy usually resolves after

immunosuppressive treatments are initiated12.

An EEG pattern called extreme delta brush (EDB) has been found to be

specific of anti-NMDAR encephalitis13. EDB is defined as a continuous delta

activity superimposed with fast activity of the delta range. It resembles

the delta activity seen in premature infants but predominantly affects the

frontal regions and is synchronous and symmetrical13,14. EDB was reported

in around one third of the patients and has been found to correlate with

more sever illness and status epilepticus13,15.

Such uniformity in clinical presentation is tampered according to age and

sex. Male patients and children more frequently have seizures as their

only initial symptom16–18.    While both male and female patients will

eventually evolve to a complete anti-NMDAR antibody-syndrome, women

who start their disease with seizures only will develop non-epileptic

symptoms    more    quickly   than   men17,16.    Additionally,   seizures   and

dyskinesias are seen more frequently at onset in children than in adults

and seizures prevalence tends to decrease with age14,16.

                                      4

Antibodies     directed     against       the   GLUA1/GLUA2     subunits

of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

(AMPA)-sensitive glutamatergic receptor

Autoimmune encephalitis with antibodies targeting the AMPA receptor

(anti-AMPAR antibodies) might present as an acute encephalopathy with

symptoms and brain MRI abnormalities either restricted to the limbic

areas, or involving both limbic or non-limbic regions19–21. Other, over-

lapping anti-neuronal antibodies are occasionally found (0 to 40%

according to the series) and influence the clinical presentation19–22.

Therefore, an important clinical variability has been observed20,21.

Seizures are not a prominent feature of AMPAR encephalitis but are

potentially harmful and may lead to prolonged status epilepticus19. Of

note, antibodies against the GluR2/3 or GLUR3 subunit alone of the AMPAR

are occasionally found in patients with Rasmussen encephalitis23 but their

relevance in the physiopathology is a matter of debate.

Antibodies targeting the Leucin-rich glioma 1 (Lgi1) protein

Anti-Lgi1 antibodies associate with an encephalitic syndrome in which two

major targets of the autoimmune process have been identified: mesial

temporal lobe (MTL) structures and motor cortex24. As a result, 2 main

types of paroxysmal neurological symptoms have been described in anti-

Lgi1 antibody-positive patients: facio-brachial dystonic seizures (FDBS),

also called dystonic/tonic seizures, and MTL seizures24–27.

FDBS are considered as pathognomonic of anti-Lgi1 encephalitis and

consist in brief (

(28%)26,27. This tonic contraction is apparent as a grimacing face and an

arm posturing, and when the leg is involved, can lead to frequent falls,

that are sometimes traumatic. FDBS can occur both at wake and during

sleep, can be provoked by physical or emotional triggers, and are rarely

preceded by a sensitive aura. FDBS are usually unilateral in the first stages

of the disease and frequently becomes bilateral later on24,26,27. When

bilateral, the 2 sides are involved independently from each other,

although contralateral FDBS may occur a short delay after the preceding
                  24,26,27
one (à bascule)              . Combined EEG/EMG recordings have shown that

FDBS originate from the motor cortex, and allowed the identification of a

specific EEG pattern consisting in a slow wave of around 700 milliseconds

of duration in the fronto-polar, frontal or central area, that immediately

precede the tonic contraction of the contralateral arm24.

Mesial temporal lobe seizures occur in 66 to 89% of the patients19,24,26–28.

They usually consist in brief, extremely frequent simple partial MTL

seizures manifesting as vegetative symptoms, intrapsychic hallucinations,

or ictal fear. Complex and generalized seizures usually appear in later

stages of the disease and are associated with cognitive impairment24,26.

FDBS are quite unresponsive to AED, and a study suggested an unusually

high frequency of severe adverse events of AED in this population of

patients24,27. However, immunotherapy, particularly steroids, was shown

to have beneficial effects on FDBS, TLS and cognitive impairment27. By

contrast, MTL seizures are usually easily controlled by antiepileptic

medications24.

Based on clinical, electrophysiological and radiological evidence, a study

suggested that at the initial stages of anti-Lgi1 encephalitis, the motor

                                        6

cortex, the MTL structures or both are affected unilaterally, and that, as

the disease progresses, the inflammatory process spreads to previously

unaffected motor cortex or MTL structures, and to the contralateral

hemisphere24. This proposed natural history would explain why FDBS can

precede or follow partial MTL seizures, and why most patients will

eventually develop a complete syndrome with bilateral FDBS, MLT seizures

and cognitive dysfunction24.

Antibodies against the contactin-2 associated protein (CASPR2)

Anti-CASPR2 antibodies are found in patients with a wide range of

autoimmune neurological syndromes, including CNS manifestations, such

as autoimmune encephalitis and hyperkinetic movement disorders, PNS

symptoms such as peripheral nerve hyperexcitability, or a combination of

both as in the Morvan’ syndrome25,29–32. The reason why such diverse

manifestations present in association with the same biomarker is

unknown; we suggested, however, that anti-CASPR2 antibody-positivity in

the CSF characterizes patients with autoimmune encephalitis, while

patients without CSF autoantibodies may only develop peripheral nerve

hyperexcitability or Morvan’s syndrome30.

Seizures are mostly seen in patients with encephalitis, consists in MTL

seizures sometimes followed by generalization, and intricate with mild or

severe anterograde amnesia and frontal lobe dysfunction30,32. Epilepsy has

been reported in 71 to 89% of the patients with anti-CASPR2 antibody-

related encephalitis30–32. Anti-CASPR2 antibody-associated encephalitis

symptoms include cerebellar ataxia in one third of the patients30,31.

Although the onset of the disease is classically acute with seizures and

anterograde amnesia, the disease generally follows a protracted course

over months or years, with fluctuations of the symptoms and partial

                                    7

response to immunotherapy30–32. The seizures are usually easily controlled

by antiepileptic medication, which, from our experience, needs to be

maintained over a long term to avoid seizure recurrence. A minority of

patients will develop refractory epilepsy30.

Antibodies targeting the dipeptidyl-peptidase protein 6 (DPPX)

Anti-DDPX antibodies are found in patients with an encephalitic syndrome

that associates digestive prodromal symptoms (profuse diarrhea and

weight loss), confusion, altered confusion and various symptoms of

cortical hyperexcitability, including tremor, hyperekplexia, myoclonic

jerks and seizures33,34. The disease usually follows a protracted course and

is generally at least partially responsive to immunotherapy34. The

prevalence of epilepsy in such patients remains unclear; generalized

seizures and status epilepticus have been reported33.

Antibodies against the glutamic acid decarboxylase isotype 65

(GAD65)

Anti-GAD65    antibodies   are   encountered    in   various   autoimmune

neurological syndromes, including cerebellar ataxia, limbic encephalitis,

and stiff person syndrome (SPS) Anti-GAD65 antibody-related encephalitis

is characterized by the prominence of MTL seizures that are usually

pharmaco-resistant35–37. Short-term memory impairment, dysexecutive

symptoms and mood disturbances are frequent accompanying features. A

study reported that around 15% of all patients with anti-GAD ab

neurological syndromes are paraneoplastic, a finding however inconsistent

with other reports36–38. According to our own experience (unpublished),

MTL epilepsy is prominent in AE with anti-GAD65 antibodies, is often

multifocal, frequently causes transient dysmnestic symptoms and is

                                     8

commonly      refractory   to   antiepileptic   medication.   While    cognitive

symptoms eventually occurred in most of our patients, they can be

delayed regarding to the onset of the seizures, and can lead to significant

long-term cognitive impairment. Aggressive immunotherapy had minor or

no effect on either seizure or cognitive outcomes, as Malter et al already

observed36.

Antibodies targeting the γ-aminobutyric acid receptor type A

(GABAAR)

Autoimmune encephalitis with anti-GABAAR antibodies affects both adults

and children and consists in acute encephalitis in most of the patients,

with partial or generalized seizures in most patients39,40. Status

epilepticus, movement disorders, decreased consciousness and cognitive

and behavioural problems are frequent. Brain MRI may shows very

distinctive multifocal and asynchronous FLAIR hyperintensities that

involving   cortical   –   subcortical   structures,   cerebellum     and   basal

ganglia39,40. Children with anti-GABAAR antibodies are more likely to

develop seizures than adults40. Most patients improve after immuno-

therapy initiation. Of note, low-titre serum anti- GABAAR antibodies have

been described in association with various neurological syndromes (anti-

GAD65 antibody-associated limbic encephalitis or SPS, non-anti-GAD65

SPS, or opsoclonus myoclonus syndrome) but their relevance in these

conditions remains unclear39.

Antibodies targeting the γ-aminobutyric acid receptor type B

(GABABR)

Anti-GABABR antibodies are found in a homogeneous group of patients, all

with an acute onset of seizures, accompanied by signs of limbic dys-

                                         9

function (confusion, behavioural disorders, anterograde amnesia)41–43.

Non-epileptic symptoms can be present initially or develop after the

appearance of seizures. Seizures can either be partial or generalized and

are often difficult to control; status epilepticus is frequent. Epilepsy

however seems to be prominent only at the earliest stages of the

disease43. About a half of the reported patients had a small cell lung

carcinoma, usually older patients and heavy smokers41–43. Most patients

improve with immunotherapy but a significant proportion will eventually

die from tumour progression42,43. In our own experience, drug-resistant

generalized seizures are usually seen in the first stage of the disease, and

are followed in 75% of the patients by confusion and status epilepticus,

after a delay of 12 days in mean (unpublished data). After this stage of

highly active epilepsy, the seizure frequency tended to decrease and the

patients to progressively develop cognitive disturbances.

Antibodies against the glycine receptor (GlyR)

Anti-GlyR antibodies were first described in patients with progressive

encephalomyelitis with rigidity and myoclonus (PERM)44. Seizures are rare

in PERM patients and are seen usually in secondary stages of the disease

rather than at the onset45. A large cohort study however, reported as

much as 13% of seizure prevalence in PERM patients with anti-GlyR

antibodies46. Additionally, anecdotal case reports of children with acute

encephalopathy and generalized or focal epilepsy with anti-GlyR anti-

bodies have been reported47–49, usually with good response to immuno-

therapy. Also, several studies have shown that anti-GlyR antibodies could

be detected in a small percentage of patients with otherwise unexplained

epilepsy50–53. These data, however disparate, suggest that a minority of

                                    10

patients with unexplained epileptic encephalopathy might harbour anti-

GlyR antibodies and may be responsive to immunotherapy.

Antibodies directed against the metabotropic receptor type 5

(mGluR5)

Anti-mGluR5 antibodies were described in no more than 3 patients with

limbic encephalitis and Hodgkin’s lymphoma (“Ophelia syndrome”)54,55. All

patients had mood and personality changes and seizures. A good recovery

was observed in all cases after treatment of the underlying cancer.

Antibodies targeting the Neurexin3α protein

Anti-Neurexin3α antibodies were recently described in 5 patients with

acute confusion, decreased consciousness, and generalized seizures that

were preceded by prodromal viral-like symptoms56. The outcome was poor

in most patients, only one of them experiencing substantial recovery after

steroid therapy. No cancer was detected in any of the patients.

Antibodies against the adenylate kinase 5 (AK5) protein

Anti-AK5 antibodies have been reported in 12 patients so far57,58.

All patients developed subacute anterograde amnesia, inconsistently

accompanied by confusion, agitation, aggressiveness and prosopagnosia.

Brain MRI displays marked bilateral FLAIR hyperintensities in the mesial

temporal lobes, evolving to severe hippocampal atrophy in all cases with

sufficient follow-up. Strikingly, seizures were never reported in patients

with anti-AK5 antibodies, except for one generalized seizure 6 months

after onset in one case57. Therefore, data available to date suggest that

anti-AK5 antibodies encephalitis presents as a seizure-free limbic

encephalitis syndrome.

                                    11

Conclusion

An increasing number of antibodies targeting neuronal antigens has been

and still continue to be described in patients with autoimmune epilepsy.

In most cases, seizures fit into an autoimmune encephalitic syndrome,

which may nonetheless become evident later than the epilepsy itself. As

clinical evidence accumulate, it appears that the clinical presentation

largely depend on the antigen targeted by the autoantibodies detected in

patients sera and/or CSF. Acknowledgment of these antibody-specific

syndromes will improve diagnosis accuracy in patients with potential

autoimmune epilepsy. However, the precise characterization of such

antibody-specific neurological syndromes is still in process. Reference

centres and on-the-ground physicians must continue to collaborate

worldwide to ensure careful prospection and analysis of clinical data and

sample

                                   12

Table. Clinical features according to anti-neuronal antibody specificity.

      Antigen            Clinical specificities                                                                      EEG pattern

      NMDAR              -   Predominantly women under 45 years, 60% ovarian teratoma                                Extreme delta brush
                         -   Stereotyped course
                         -   Initial symptoms differ according to age and sex
                         -   Seizures are sometimes difficult to distinguish from abnormal movements

      AMPAR              -   Variable presentation, potentially harmful
                         -   Epilepsy is inconsistent
                         -   Frequently, different auto-antibodies overlap

      Lgi1               -   Two types of seizures: mesial temporal lobe and facio-brachial dystonic seizures        Slow wave in the fronto-central areas that
                         -   Responsive to early steroid and immunosuppressive treatments                            precede facio-brachial dystonic seizures

13
      CASPR2             -   Protracted course
                         -   Male predominance
                         -   Temporal lobe epilepsy is frequent

      DPPX               -   Cortical hyperexcitability symptoms: tremor, hyperekplexia, myoclonic jerks, seizures
                         -   Digestive tract symptoms

      GAD65              Chronic encephalopathy with temporal lobe epilepsy, usually refractory to antiepileptic
                         and immunosuppressive medications

      GABAAR             -   Seizures are seen in most patients, status epilepticus is frequent
                         -   Multifocal lesions on brain MRI

      GABABR             Epilepsy is highly active on the initial stages, becomes less active on later stages
                         while cognitive symptoms develop.

      Glycine Receptor   -   Associates with PERM, in which seizures are inconsistent
                         -   Rarely found in patients with cryptogenic epileptic encephalopathy

      AK5                Limbic encephalitis without seizure

References

1. Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies.
   Ann N Y Acad Sci. Epub 2014 Oct 14.
2. Giometto B, Grisold W, Vitaliani R, Graus F, Honnorat J, Bertolini
   G. Paraneoplastic neurologic syndrome in the PNS Euronetwork
   database: a European study from 20 centers. Arch Neurol.
   2010;67:330–335.
3. Graus F, Delattre J, Antoine J, et al. Recommended diagnostic
   criteria for paraneoplastic neurological syndromes. J Neurol
   Neurosurg Psychiatry. 2004;75:1135–1140.
4. Honnorat J, Antoine JC, Derrington E, Aguera M, Belin MF.
   Antibodies to a subpopulation of glial cells and a 66 kDa
   developmental protein in patients with paraneoplastic neurological
   syndromes. J Neurol Neurosurg Psychiatry. 1996;61:270–278.
5. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-
   Ma2-associated encephalitis. Brain J Neurol. 2004;127:1831–1844.
6. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau
   J. Paraneoplastic limbic encephalitis: neurological symptoms,
   immunological findings and tumour association in 50 patients.
   Brain J Neurol. 2000;123 ( Pt 7):1481–1494.
7. Gadoth A, Kryzer TJ, Fryer J, McKeon A, Lennon VA, Pittock SJ.
   Microtubule-associated protein 1B: Novel paraneoplastic biomarker.
   Ann Neurol. 2017;81:266–277.
8. Honnorat J, Cartalat-Carel S, Ricard D, et al. Onco-neural
   antibodies and tumour type determine survival and neurological
   symptoms in paraneoplastic neurological syndromes with Hu or
   CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry.
   2009;80:412–416.
9. Ganor Y, Goldberg-Stern H, Blank M, et al. Antibodies to glutamate
   receptor subtype 3 (GluR3) are found in some patients suffering
   from epilepsy as the main disease, but not in patients whose
   epilepsy accompanies antiphospholipid syndrome or Sneddon’s
   syndrome. Autoimmunity. 2005;38:417–424.
10. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis
   of autoimmune encephalitis. Lancet Neurol. 2016;15:391–404.
11. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR,
   Balice-Gordon R. Clinical experience and laboratory investigations
   in patients with anti-NMDAR encephalitis. Lancet Neurol.
   2011;10:63–74.

                                 14

12. De Montmollin E, Demeret S, Brulé N, et al. Anti-N-Methyl-d-
   Aspartate Receptor Encephalitis in Adult Patients Requiring
   Intensive Care. Am J Respir Crit Care Med. 2017;195:491–499.
13. Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J,
   Friedman D. Extreme delta brush: a unique EEG pattern in adults
   with anti-NMDA receptor encephalitis. Neurology. 2012;
   79:1094–1100.
14. Armangue T, Titulaer MJ, Málaga I, et al. Pediatric anti-N-methyl-
   D-aspartate receptor encephalitis-clinical analysis and novel
   findings in a series of 20 patients. J Pediatr. 2013;162:850–856.e2.
15. Veciana M, Becerra JL, Fossas P, et al. EEG extreme delta brush:
   An ictal pattern in patients with anti-NMDA receptor encephalitis.
   Epilepsy Behav EB. 2015;49:280–285.
16. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and
   prognostic factors for long-term outcome in patients with anti-
   NMDA receptor encephalitis: an observational cohort study. Lancet
   Neurol. 2013;12:157–165.
17. Viaccoz A, Desestret V, Ducray F, et al. Clinical specificities of
   adult male patients with NMDA receptor antibodies encephalitis.
   Neurology. 2014;82:556–563.
18. Zekeridou A, Karantoni E, Viaccoz A, et al. Treatment and outcome
   of children and adolescents with N-methyl-D-aspartate receptor
   encephalitis. J Neurol. 2015;262:1859–1866.
19. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic
   encephalitis alter synaptic receptor location. Ann Neurol.
   2009;65:424–434.
20. Joubert B, Kerschen P, Zekeridou A, et al. Clinical Spectrum of
   Encephalitis Associated With Antibodies Against the α-Amino-3-
   Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor: Case Series
   and Review of the Literature. JAMA Neurol. 2015;72:1163–1169.
21. Höftberger R, van Sonderen A, Leypoldt F, et al. Encephalitis and
   AMPA receptor antibodies: Novel findings in a case series of 22
   patients. Neurology. 2015;84:2403–2412.
22. Dogan Onugoren M, Deuretzbacher D, Haensch CA, et al. Limbic
   encephalitis due to GABAB and AMPA receptor antibodies: a case
   series. J Neurol Neurosurg Psychiatry. Epub 2014 Oct 9.

                                  15

23. Nibber A, Clover L, Pettingill P, et al. Antibodies to AMPA receptors
   in Rasmussen’s encephalitis. Eur J Paediatr Neurol EJPN Off J Eur
   Paediatr Neurol Soc. 2016;20:222–227.
24. Navarro V, Kas A, Apartis E, et al. Motor cortex and hippocampus
   are the two main cortical targets in LGI1-antibody encephalitis.
   Brain. 2016;139:1079–1093.
25. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium
   channel-complex proteins leucine-rich, glioma inactivated
   1 protein and contactin-associated protein-2 in limbic encephalitis,
   Morvan’s syndrome and acquired neuromyotonia. Brain.
   2010;133:2734–2748.
26. Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures
   precede Lgi1 antibody limbic encephalitis. Ann Neurol.
   2011;69:892–900.
27. Irani SR, Stagg CJ, Schott JM, et al. Faciobrachial dystonic seizures:
   the influence of immunotherapy on seizure control and prevention
   of cognitive impairment in a broadening phenotype. Brain.
   2013;136:3151–3162.
28. Van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1
   encephalitis: Clinical syndrome and long-term follow-up.
   Neurology. 2016;87:1449–1456.
29. Lancaster E, Huijbers MG, Bar V, et al. Investigations of Caspr2, an
   autoantigen of encephalitis and neuromyotonia. Ann Neurol.
   2011;69:303–311.
30. Joubert B, Saint-Martin M, Noraz N, et al. Characterization of a
   Subtype of Autoimmune Encephalitis With Anti-Contactin-
   Associated Protein-like 2 Antibodies in the Cerebrospinal Fluid,
   Prominent Limbic Symptoms, and Seizures. JAMA Neurol.
   2016;73:1115–1124.
31. Van Sonderen A, Ariño H, Petit-Pedrol M, et al. The clinical
   spectrum of Caspr2 antibody-associated disease. Neurology.
   2016;87:521–528.
32. Bien CG, Mirzadjanova Z, Baumgartner C, et al. Anti-contactin-
   associated protein-2 encephalitis: relevance of antibody titres,
   presentation and outcome. Eur J Neurol. 2017;24:175–186.
33. Boronat A, Gelfand JM, Gresa-Arribas N, et al. Encephalitis and
   antibodies to dipeptidyl-peptidase-like protein-6, a subunit of
   Kv4.2 potassium channels. Ann Neurol. 2013;73:120–128.
34. Hara M, Ariño H, Petit-Pedrol M, et al. DPPX antibody-associated
   encephalitis: Main syndrome and antibody effects. Neurology.
   2017;88:1340–1348.

                                 16

35. Saiz A, Blanco Y, Sabater L, et al. Spectrum of neurological
   syndromes associated with glutamic acid decarboxylase antibodies:
   diagnostic clues for this association. Brain J Neurol. 2008;
   131:2553–2563.
36. Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG.
   Antibodies to glutamic acid decarboxylase define a form of limbic
   encephalitis. Ann Neurol. 2010;67:470–478.
37. Falip M, Carreño M, Miró J, et al. Prevalence and immunological
   spectrum of temporal lobe epilepsy with glutamic acid
   decarboxylase antibodies. Eur J Neurol. 2012;19:827–833.
38. Ariño H, Höftberger R, Gresa-Arribas N, et al. Paraneoplastic
   Neurological Syndromes and Glutamic Acid Decarboxylase
   Antibodies. JAMA Neurol. 2015;72:874–881.
39. Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with
   refractory seizures, status epilepticus, and antibodies to the GABAA
   receptor: a case series, characterisation of the antigen, and
   analysis of the effects of antibodies. Lancet Neurol. 2014;
   13:276–286.
40. Spatola M, Petit-Pedrol M, Simabukuro MM, et al. Investigations in
   GABAA receptor antibody-associated encephalitis. Neurology.
   2017;88:1012–1020.
41. Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B)
   receptor in limbic encephalitis with seizures: case series and
   characterisation of the antigen. Lancet Neurol. 2010;9:67–76.
42. Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABA(B) receptor
   antibodies in limbic encephalitis and anti-GAD-associated
   neurologic disorders. Neurology. 2011;76:795–800.
43. Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB
   receptor antibodies: novel findings in a new case series of 20
   patients. Neurology. 2013;81:1500–1506.
44. Hutchinson M, Waters P, McHugh J, et al. Progressive
   encephalomyelitis, rigidity, and myoclonus: a novel glycine
   receptor antibody. Neurology. 2008;71:1291–1292.
45. McKeon A, Martinez-Hernandez E, Lancaster E, et al. Glycine
   receptor autoimmune spectrum with stiff-man syndrome
   phenotype. JAMA Neurol. 2013;70:44–50.
46. Carvajal-González A, Leite MI, Waters P, et al. Glycine receptor
   antibodies in PERM and related syndromes: characteristics, clinical
   features and outcomes. Brain J Neurol. 2014;137:2178–2192.
47. Ude C, Ambegaonkar G. Glycine receptor antibody-associated
   epilepsy in a boy aged 4 years. BMJ Case Rep. 2016;2016.

                                17

48. Wuerfel E, Bien CG, Vincent A, Woodhall M, Brockmann K. Glycine
   receptor antibodies in a boy with focal epilepsy and episodic
   behavioral disorder. J Neurol Sci. 2014;343:180–182.
49. Chan DWS, Thomas T, Lim M, Ling S, Woodhall M, Vincent A. Focal
   status epilepticus and progressive dyskinesia: A novel phenotype
   for glycine receptor antibody-mediated neurological disease in
   children. Eur J Paediatr Neurol EJPN Off J Eur Paediatr Neurol Soc.
   2017;21:414–417.
50. Baysal-Kirac L, Tuzun E, Erdag E, et al. Neuronal autoantibodies in
   epilepsy patients with peri-ictal autonomic findings. J Neurol.
   2016;263:455–466.
51. Vanli-Yavuz EN, Erdag E, Tuzun E, et al. Neuronal autoantibodies in
   mesial temporal lobe epilepsy with hippocampal sclerosis. J Neurol
   Neurosurg Psychiatry. 2016;87:684–692.
52. Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic
   autoantibodies in cohorts of patients with new and established
   epilepsy. Epilepsia. 2013;54:1028–1035.
53. Ekizoglu E, Tuzun E, Woodhall M, et al. Investigation of neuronal
   autoantibodies in two different focal epilepsy syndromes.
   Epilepsia. 2014;55:414–422.
54. Lancaster E, Martinez-Hernandez E, Titulaer MJ, et al. Antibodies
   to metabotropic glutamate receptor 5 in the Ophelia syndrome.
   Neurology. 2011;77:1698–1701.
55. Prüss H, Rothkirch M, Kopp U, et al. Limbic encephalitis with
   mGluR5 antibodies and immunotherapy-responsive prosopagnosia.
   Neurology. 2014;83:1384–1386.
56. Gresa-Arribas N, Planagumà J, Petit-Pedrol M, et al. Human
   neurexin-3α antibodies associate with encephalitis and alter
   synapse development. Neurology. 2016;86:2235–2242.
57. Tüzün E, Rossi JE, Karner SF, Centurion AF, Dalmau J. Adenylate
   kinase 5 autoimmunity in treatment refractory limbic encephalitis.
   J Neuroimmunol. 2007;186:177–180.
58. Do L-D, Chanson E, Desestret V, et al. Characteristics in limbic
   encephalitis with anti-adenylate kinase 5 autoantibodies.
   Neurology. 2017;88:514–524.

                                 18